Congestive heart failure is a primary cardiac disease that affects roughly 1% of the US population. Mortality in the first five years subsequent to diagnosis ranges from 35-60%. The primary cause of mortality during this period is a severe electrical arrhythmia known as Sudden Cardiac death (SCD). the cuases of SCD are unknown. The objective of this resarch is to undertake a joint modeling and experimental study directed at developing quantitative computer models of electrical excitation, propagation, and repolarization in the failing heart in order to better understand the origins and prevention of SCD. The canine tachycardia pacing-induced animal model of heart failure is used, as this model yields hemodynamic and electrical changes in the canine heart which are strikingly similar to those seen in human patients. Aim 1 will formulate a computer model of the normal canine isolated ventricular cell action potential, and use this model in conjunction with experiments to examine dependence of action potential shape and duration on intracellular calcium handling processes, and repolarizing membrane currents. Aim 2 will develop a computer model of the failing canine ventricular myocyte and will use the model to investigate whether or not the altered expression of repolarizing membrane currents and proteins involved in intracellular calcium handling known to occur during heart failure can account for action potentials and intracellular calcium transients measured in failing cells. Aim 3 will undertake a combined modeling and experimental study investigating three possible sources of arrhythmia in failing cells: a) early afterdepolarizations; b) oscillatory pre-potentials; and c) altered expression of the If pacemaker current. Aim 4 will use diffusion tensor magnetic resonance imaging to measure changes in anatomical structure of normal versus failing canine hearts. These structural data will be used in conjunction with the models developed in Aims 1-3 to investigate electrical excitation, propagation, and repolarization in three-dimensional models of the failing canine ventricles. These computer models will also be used to investigate the ways in which ventricular dilatation, wall thinning, and possible alteration of fiber orientation and/or fiber rotation gradient alter electrical conduction in the failing heart. The arrhythmogenic potential of the cellular mechanisms investigated in Aim 3 will be tested using the three-dimensional ventricular models.